Upper aerodigestive tract (UADT) tumors present different biological behavior and prog-38 nosis, suggesting specific molecular mechanisms underlying their development. However, they are 39 rarely considered as single entities (particularly head and neck subsites) and share the most com-40 mon genetic alterations. Therefore, there is a need for a better understanding of the global DNA 41 methylation differences among UADT tumors. We performed a genome-wide DNA methylation 42 analysis of esophageal (ESCC), laryngeal (LSCC), oral (OSCC) and oropharyngeal (OPSCC) squa-43 mous cell carcinomas, and their non-tumor counterparts. The unsupervised analysis showed that 44 non-tumor tissues present markedly distinct DNA methylation profiles, while tumors are highly 45 heterogeneous. Hypomethylation was more frequent in LSCC and OPSCC, while ESCC and OSCC 46 presented mostly hypermethylation, with the latter showing a CpG island overrepresentation. Dif-47 ferentially methylated regions affected genes in 127 signaling pathways, with only 3.1% of these being common among different tumor subsites, but with different genes affected. The WNT signal-49 ing pathway, known to be dysregulated in different epithelial tumors, is a frequent hit for DNA 50 methylation and gene expression alterations in ESCC and OPSCC, but mostly for genetic alterations 51 in LSCC and OSCC. UADT tumor subsites present differences in genome-wide methylation regard-52 ing their profile, intensity, genomic regions and signaling pathways affected.